(Applicant's Abstract) The "new BPD" seen in infants of < 1000g is characterized by pathologic changes hypothesized to arise from injury to the lung that lead to inflammation and increased susceptibility to infection. These in turn are proposed to interrupt pulmonary development, especially retarding alveolarization and angiogenesis. The consequence is pulmonary insufficiency, resulting in difficult oxygenation and susceptibility to nosocomial infection. This BPD is difficult to prevent or treat and, paradoxically, its incidence is increasing because of improved survival of these infants. Recent evidence indicates that the syndecans, highly abundant cell surface heparan sulfate proteoglycans (HSPGs), modulate inflammation and host defense. These transmembrane proteins have extracellular domains (ectodomains) that bear HS chains near their N-termini, distant from the plasma membrane. Syndecans are on the surface of every adherent cell where, by virtue of the high affinity of their HS chains for proteins, they act as co-receptors for molecules involved in the repair of injury and host defense. Syndecan-1 and -4 are induced in the lung in response to hyperoxia, and agents produced during tissue injury cause their ectodomains to be shed into inflammatory fluids (skin wound fluids, tracheal aspirates from ventilated infants and baboons) where they can modify growth factor and proteolytic balance. Both syndecan-1 null mice and mice that transgenically overexpress syndecan-1 under a broadly acting promotor show defective wound repair; the null mice are impaired in epithelial repolarization and the overexpressing mice excessively shed syndecan-1 ectodomains, which alter cell proliferation and proteolytic activity in the wound. A known Pseudomonas aeruginosa virulence factor accelerates syndecan-1 shedding in the lung where the ectodomain enhances the microbe?s virulence, presumably by interfering with host defenses. This grant is designed to test the hypothesis that excessive shedding of syndecan ectodomains contributes to the pathogenesis of BPD, a previously unappreciated role that provides new approaches to preventive and/or therapeutic interventions. To explore this hypothesis, the investigators aim to i) use transgenic and null mice to establish the regulatory role of syndecans in the response to lung injury in the mouse; ii) determine the mechanisms of syndecan-1 and -4 induction and shedding in response to lung injury; iii) Evaluate consequences of syndecan ectodomain shedding for pulmonary inflammation and host defense; iv) correlate clinical outcomes of pre-term ventilated infants with their tracheal aspirate levels and activities of syndecan-1 and -4 ectodomains.